The proposed research will explore the pharmacology of flurazepam (Dalmane) as it relates to abuse, tolerance and dependence. The results of the research will be important for understanding problems that may be specific to flurazepam abuse and dependence, and, since all the benzodiazepines have similar actions, the results will also be important to understanding the long-term effects of diazepam and other benzodiazepines. The experiments will continue our studies of the dose and time requirements for producing tolerance and physical dependence. Tolerance will be carefully quantitated using newly developed techniques for measuring thelevels of flurazepam and its metabolites in biofluids. We will compare the tolerance developed to different actions of flurazepam, namely: locomotor impairment, muscle relaxation, anticonvulsant action and ability to increase responding in a conflict behavior test. Abstinence phenomena will be carefully described, and the importance of elimination kinetics in the expression of the abstinence syndrome will be examined. In an attempt to understand the changes that have occurred during treatment, synaptic function will be studied in the spinal cord reflexes of chronically treated animals. A major goal of the research is to explore the interactions between benzodiazepines and barbiturates, both in acute and chronic treatments. This will be done in intact animals, and also in the spinal reflexes of animals that are tolerant to and dependent on pentobarbital. Cross-tolerance between these two classes of drugs, as well as with other types of depressants, will be studied. We will also examine the loss of specific benzodiazepine binding sites (probably receptors) as a mechanism for tolerance and dependence. At the same time, the GABA receptor system will be examined since there is a functional link between it and the benzodiazepine binding site. By using a variety of techniques, and by comparing the results of each, we hope to eventually understand how the nervous system responds to repeated exposure to benzodiazepines. Since these are the most widely prescribed psychoactie drugs, and since their overuse is a recognized major health problem, the results of this research are expected to have not only theoretical, but also clinical significance.